PROJECT SUMMARY The proposed studies will dissect the role of Reactive Astrocytes (RAs) in Alzheimer?s Disease (AD). Common to virtually all neurodegenerative diseases and brain disorders are changes in glial cells called astrocytes, which become ?reactive?. Astrocytes ordinarily provide critical support for neurons and only turn into RAs following injury or development of disease. A longstanding issue which has re- mained unknown is whether RAs contribute to, or help alleviate, Alzheimer?s Disease progression. The long-term goal of our research is to increase understanding of the molecular and cellular underpinnings of AD and Alzheimer?s Disease Related Dementias through increased understanding of the role of re- active astrocytes. The objective of this proposal is to deliver a new strategy to selectively alter (elimi- nate, increase, or decrease) gene expression only in RAs at any point during the progression of AD. Despite being one of the most common neurological diseases, the mechanisms underlying synaptic loss and cognitive decline in AD are poorly understood. It is critical to gain new insights into AD mecha- nisms if new treatment targets are to be developed. Two aims are proposed, with the goal of character- izing our new strategy and providing proof-of-principle for using the approach to selectively target and manipulate RAs in AD: In Aim 1, a novel reactive astrocyte inducible Cre transgenic strategy to selec- tively manipulate RAs in AD will be characterized for specificity of expression in reactive cell types in the diseased brain. In Aim 2, the new strategy will be used to either selectively eliminate RAs or repro- gram them back into non-reactive astrocytes at various stages during the development of AD. The pro- posed work will provide new knowledge on the protective vs. detrimental roles of reactive astrocytes in the development and progression of AD. The rationale for the proposed research is that new knowledge on the role of reactive cell types in AD is an important goal for the development of more effi- cacious treatments. It is anticipated that this research will be transformative, as a powerful new strategy will be introduced to the research community to investigate the role of reactive astrocytes in Alzheimer?s Disease, and potentially any disease or disorder of the nervous system.